Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University.
Center for Infectious Disease Education and Research (CiDER), Osaka University.
Biol Pharm Bull. 2023;46(12):1753-1760. doi: 10.1248/bpb.b23-00482.
A systemic inflammatory response leads to widespread organ dysfunction, such as kidney dysfunction. Plasminogen activator inhibitor-1 (PAI-1) is involved in the pathogenesis of inflammatory kidney injury; however, the regulatory mechanism of PAI-1 in injured kidneys remains unclear. PAI-1 is induced by interleukin (IL)-6 in patients with sepsis. In addition, the stabilization of IL-6 is regulated by the adenine-thymine-rich interactive domain-containing protein 5a (Arid5a). Therefore, the aim of the present study was to examine the involvement of Arid5a/IL-6/PAI-1 signaling in lipopolysaccharide (LPS)-induced inflammatory kidney injury. LPS treatment to C57BL/6J mice upregulated Pai-1 mRNA in the kidneys. Enzyme-linked immunosorbent assay (ELISA) revealed that PAI-1 expression was induced in the culture supernatants of LPS-treated human umbilical vein endothelial cells, but not in those of LPS-treated human kidney 2 (HK-2) cells, a tubular cell line. Combined with single-cell analysis, endothelial cells were found to be responsible for PAI-1 elevation in LPS-treated kidneys. Administration of TM5441, a PAI-1 inhibitor, reduced the urinary albumin/creatinine ratio, concomitant with downregulation of Il-6 and Arid5a mRNA expressions. IL-6 treatment in LPS model mice further upregulated Pai-1 mRNA expression compared with LPS alone, accompanied by renal impairment. Furthermore, the expression of Il-6 and Pai-1 mRNA was lower in Arid5a knockout mice than in wild-type mice after LPS treatment. Taken together, the vicious cycle of Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.
全身性炎症反应导致广泛的器官功能障碍，如肾功能障碍。纤溶酶原激活物抑制剂-1（PAI-1）参与了炎症性肾损伤的发病机制；然而，PAI-1 在受损肾脏中的调节机制尚不清楚。PAI-1 在脓毒症患者中由白细胞介素（IL）-6 诱导。此外，IL-6 的稳定受富含腺嘌呤-胸腺嘧啶的相互作用域蛋白 5a（Arid5a）调节。因此，本研究旨在研究 Arid5a/IL-6/PAI-1 信号通路在脂多糖（LPS）诱导的炎症性肾损伤中的作用。LPS 处理 C57BL/6J 小鼠可上调肾脏中的 Pai-1 mRNA。酶联免疫吸附试验（ELISA）显示，LPS 处理的人脐静脉内皮细胞培养上清液中诱导了 PAI-1 表达，但 LPS 处理的肾小管细胞系人肾 2（HK-2）细胞中未诱导。结合单细胞分析，发现内皮细胞是 LPS 处理的肾脏中 PAI-1 升高的原因。PAI-1 抑制剂 TM5441 的给药降低了尿白蛋白/肌酐比，同时下调了 Il-6 和 Arid5a mRNA 的表达。与 LPS 单独处理相比，IL-6 处理 LPS 模型小鼠进一步上调了 Pai-1 mRNA 的表达，同时伴有肾功能损害。此外，与野生型小鼠相比，LPS 处理后 Arid5a 敲除小鼠的 Il-6 和 Pai-1 mRNA 表达水平较低。综上所述，Arid5a/IL-6/PAI-1 信号通路的恶性循环参与了 LPS 诱导的肾脏损伤。
